Dr Rini on the FDA Approval of Belzutifan in Relapsed/Refractory RCC

Brian I. Rini, MD, FASCO, Ingram Professor of Medicine, Department of Medicine, Division of Hematology Oncology, Vanderbilt University, chief, Clinical Trials, Vanderbilt-Ingram Cancer Center, make sure the institution name is changed in the lower third too discusses the importance of the FDA approval of belzutifan (Welireg) in patients with relapsed/refractory renal cell carcinoma (RCC). 

 for the treatment of patients with RCC who have progressed on a previous PD-1 or PD-L1 inhibitor and a VEGF TKI. This regulatory decision was supported by data from the phase 3 LITESPARK-005 trial (NCT04195750), in which patients experienced a statistically significant improvement in progression-free survival (PFS) with belzutifan compared with everolimus (Afinitor; HR, 0.75; 95% CI, 0.63-0.90; 1-sided 

 = .0008). The median PFS was 5.6 months (95% CI, 3.9-7.0) with belzutifan vs 5.6 months (95% CI, 4.8-5.8) with everolimus.

With the approval of belzutifan, another effective treatment option is now available in the refractory RCC setting, Rini begins. It's always beneficial to have more active drugs; this approval is a positive development overall, he says. Each patient may respond differently to various treatments and tolerate them differently, making certain treatments more suitable for specific patients, Rini shares. Therefore, much work remains to be done to determine which patients benefit most from which therapies and how to apply these treatments most effectively, according to Rini. Future trials and continued clinical use of these agents may answer some of these questions, he explains.

Nonetheless, the addition of a well-tolerated, active drug is always welcome, particularly in the refractory kidney cancer setting, Rini continues. Looking ahead, apart from identifying disease subsets that are particularly susceptible to belzutifan treatment, ongoing trials are exploring combination regimens with this agent in both the second- and first-line settings, he adds. The tolerability of belzutifan makes it a promising candidate for combination regimens, although data on this are currently lacking, Rini elucidates.

Hopefully, the next couple years will provide more information about the efficacy of belzutifan in earlier lines of treatment and in combination regimens, potentially leading to its integration into earlier stages of the disease and various combination settings, Rini concludes.

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Brian I. Rini, MD, FASCO, shares the importance of the FDA approval of belzutifan in patients with advanced renal cell carcinoma.

Dr Rini on the Utility of Belzutifan in RCC

Brian I. Rini, MD, FASCO, Ingram Professor of Medicine, Division of Hematology Oncology, chief, Clinical Trials, Vanderbilt-Ingram University Cancer Center, discusses 

the background that led to the FDA approval of belzutifan

 (Welireg) for the treatment of patients with advanced renal cell carcinoma (RCC). 

Belzutifan is a well-tolerated medication, generally associated with better tolerability than most TKIs, Rini begins. Its distinctive adverse effects (AEs) primarily include anemia, which arises due to the inhibition of HIF, a gene responsible for erythropoietin and hemoglobin production, which belzutifan targets, he explains. Fortunately, anemia is relatively easy to manage with growth factors or by temporarily withholding the medication, Rini reports. Unlike anemia induced by other therapies in different diseases, belzutifan-associated anemia is typically straightforward to handle and aligns with the drug’s mechanism of action, he states.

Hypoxia is a rarer occurrence and can usually be managed by adjusting the dosage of belzutifan without requiring additional interventions, Rini expands. This AE is somewhat unique to belzutifan, as hypoxia is not commonly associated with other agents. Overall, belzutifan is generally well tolerated, as evidenced by long-term usage in patients with von Hippel-Lindau syndrome, some of whom have been receiving the medication for several years without significant long-term AEs, he says.

In refractory patient populations, where patients often experience more pronounced symptoms from their disease and may have endured multiple prior treatments, tolerability becomes a crucial factor in treatment selection, Rini elucidates. The approval of belzutifan provides another valuable treatment option in this challenging setting, he explains. Each patient may respond differently to treatments and exhibit varying levels of tolerance, making it essential to tailor treatments to individual needs, according to Rini.

Although identifying the specific patient subsets that benefit most from belzutifan remains an ongoing task, trials in progress, particularly those exploring combination therapies in both the first- and second-line settings, hold promise, he continues. Belzutifan's favorable tolerability profile makes it well suited for combination approaches, and forthcoming data may elucidate its potential in earlier disease stages and in combination regimens, Rini concludes.

Brian I. Rini, MD, FASCO, discusses the background that led to the FDA approval of belzutifan for patients with advanced renal cell carcinoma.

Dr Rini on the Background of the FDA Approval of Belzutifan in RCC

Brian I. Rini, MD, FASCO, Ingram Professor of Medicine, Division of Hematology Oncology, chief, Clinical Trials, Vanderbilt-Ingram University Cancer Center, discusses the background that led to the FDA approval of belzutifan (Welireg) for the treatment of patients with advanced renal cell carcinoma (RCC).

On December 14, 2023, the FDA granted approval to belzutifan

 for the treatment of patients with advanced RCC who have undergone treatment with a PD-1 or PD-L1 inhibitor and a VEGF TKI. The efficacy of belzutifan was assessed in the randomized phase 3 LITESPARK-005 trial (NCT04195750), which demonstrated a statistically significant enhancement in progression-free survival (PFS) with belzutifan compared with everolimus (Afinitor; HR, 0.75; 95% CI, 0.63-0.90; 1-sided 

 = .0008). The median PFS was 5.6 months (95% CI, 3.9-7.0) with belzutifan as opposed to 5.6 months (95% CI, 4.8-5.8) with everolimus.

Although overall survival (OS) data are still incomplete in the present analysis, with 59% of deaths reported, there is no observed trend indicating an OS disadvantage with belzutifan. Additionally, a descriptive evaluation of patient-reported symptom and functional outcomes favored belzutifan over everolimus.

The LITESPARK-005 trial predominantly enrolled patients in the third and fourth-line settings, representing a refractory population of patients with kidney cancer who had experienced disease progression on previous immune and VEGF TKI therapies, Rini begins. This patient population aligns with the typical profile of patients in such settings, he adds. Notably, although the PFS curves of each arm initially overlapped with each other, indicating no difference in median PFS, a subset of patients experienced a more significant benefit with belzutifan, resulting in a notable divergence in the belzutifan curve and an HR significantly below 1, Rini explains.

Although an OS advantage with belzutifan has not yet been established, there is a disparity in median OS between the 2 arms, he expands, and further data maturation may shed light on potential OS benefits with belzutifan. Prolonged OS has historically been challenging to demonstrate in this refractory setting, Rini elucidates. Nonetheless, considering the favorable tolerability profile, PFS data, and partial quality of life data with belzutifan, this agent represents a promising addition to the RCC treatment armamentarium, he emphasizes. Additionally, addressing remaining unmet needs in refractory kidney cancer, particularly with the development of efficacious drugs, remains crucial, Rini concludes.

Brian I. Rini, MD, FASCO, discusses the research that led to the FDA approval of belzutifan for patients with advanced renal cell carcinoma.

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Brian Rini, MD

Articles

Dr Rini on the FDA Approval of Belzutifan in Relapsed/Refractory RCC

Dr Rini on the Utility of Belzutifan in RCC

Dr Rini on the Background of the FDA Approval of Belzutifan in RCC

Breaking Down the Data in Genitourinary, Gastrointestinal, and Breast Cancers, Plus Sarcoma and Melanoma at ASCO 2023: Drs Rini, Lewis, Trent, Luke, Kunz, and Lustberg